For many types of cancer, the precision of surgical resection directly influences patient prognosis. Unfortunately, intra-operative identification of tumor margins or small foci of cancer cells remains imprecise or depends on surgical judgment. Thus, the extent of surgical resection is constrained by the requirement to avoid harming vital structures. Nowhere is this more problematic than in the brain, where greater than 80% of malignant cancers recur at the surgical margin. Despite advances in intra-operative monitoring and image guidance, post-operative scans sometimes reveal bulky residual tumor that may have been resected if the surgeon had improved tools to distinguish tumor tissue from normal brain. Recent advances in molecular biology, genomics and proteomics have yielded information about molecules that are expressed in malignant cells but not adjacent tissue. This information has the potential to fundamentally transform surgical oncology if used to specifically “paint” tumor cells with targeted molecular beacons.
Matrix metalloproteinase (MMP-2) is highly expressed in many common human malignancies including glioma, melanoma, sarcoma, breast cancer, colon adenocarcinoma, prostate cancer, neuroectodermal tumors, and ovarian cancer. MMP-2 and other MMP family members are believed to contribute to cancer invasion by proteolytic degrading adjacent non-neoplastic tissue.
Isolated from the scorpion Leiurus quinquestriatus, chlorotoxin (CTX) is a 36 amino acid peptide that was initially characterized as a ligand that blocked reconstituted chloride channels. It was thought that CTX inhibited glioma cell migration by blocking glioma-specific chloride channels, but this activity was subsequently attributed to CTX-mediated inhibition of MMP-2. Chlorotoxin binds preferentially to glioma cells compared to normal brain. A radiopharmaceutical bound to a synthetic chlorotoxin, 131I-TM-601, was recently approved for Phase I/II clinical trials for brain cancer therapy based on an acceptable safety profile in preclinical studies.
Cyanine compounds are molecular beacons that emit light in the near infrared (NIR) spectrum. Because light at this wavelength are minimally absorbed by water or hemoglobin, NIR beacons are well-suited for intra-operative imaging. Previous attempts to image brain tumors by NIR have focused on targeting the probe to inflammatory microglia around the tumor or utilizing probes that require proteolytic cleavage for activation. The former approach is problematic because the presence of microglia correlates poorly, if at all, with margins of many brain tumors. Furthermore, to reduce perioperative brain edema, patients are treated with dexamethasone which is a potent inhibitor of microglial activation.
Despite the advances in the development of probes for targeting and imaging brain tumors and in view of the factors noted above, there exists a need for a probe that does not require enzymatic cleavage and that allows for intra-operative visualization of cancerous tissues. The present invention seeks to fulfill this need and provides further related advantages.